Methods and compositions for the dietary management of autoimmune disorders

ABSTRACT

The present invention describes the use of lactic acid bacteria, particularly lactic acid producing members of the genus  Bacillus , in treating digestive-related immune disorders by downregulating of cytokines and by inhibiting pathogenic or deleterious microorganisms in the gastrointestinal tract. Specific formulations of  Bacillus coagulans  for various immune disorders are elaborated.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 60/569,952, filed May 11, 2004 (pending) and U.S. ProvisionalApplication Ser. No. 60/571,553, filed May 13, 2004, (pending), thedisclosures of which are hereby incorporated by reference herein intheir entireties.

BACKGROUND OF THE INVENTION

The invention relates to the treatment of autoimmune disorders.

Gastrointestinal microflora play a number of vital roles in maintaininggastrointestinal tract function and overall physiological health.Perturbations in gastrointestinal function are associated with the onsetand progression of immune system disorders, including autoimmunedisorders. Autoimmune disorders develop when the immune system mounts animmune response against normal body tissues. Normally, the immune systemis capable of differentiating “self” from “non-self” tissue. Autoimmunedisorders occur when the normal control process is disrupted. They mayalso occur if normal body tissue is altered so that it is no longerrecognized as “self.” Microorganisms, such as pathogenic bacteria,fungi, and viruses, and other causes (drugs, alcohol, smoking, stress)trigger some of these changes, particularly in people with a geneticpredisposition to an autoimmune disorder. Autoimmune disorders result indestruction of one or more types of body tissues, abnormal growth of anorgan, or changes in organ function. The disorder may affect only oneorgan or tissue type or may affect multiple organs and tissues. Organsand tissues commonly affected by autoimmune disorders include bloodcomponents such as red blood cells, blood vessels, connective tissues,endocrine glands such as the thyroid or pancreas, muscles, joints, andskin.

Psoriasis is a chronic, genetically-influenced autoimmune disorder, mostcommon in people in their 20s, 30s, and 40s. Psoriasis is rare under age3. In the United States, two or three out of every 100 people sufferfrom psoriasis. Current topical psoriasis treatments use emollients,keratolytic agents, coal tar, anthralin, corticosteroids, andcalpotriene. These approaches have variable efficacy, fail to preventfrequent relapses, and are often associated with adverse side effects.Current systemic treatments are usually reserved for patients withphysically, socially, or economically disabling psoriasis that has notresponded to topical treatment, and often include phototherapy and/orantifungal drugs, the latter of which can only be used for short periodsof time due to toxicity and adverse side effects. Accordingly, there isa need for an effective systemic psoriasis treatment that avoids thedisadvantages associated with current topical and systemic treatments.

SUMMARY OF THE INVENTION

The invention provides a method of reducing a symptom of psoriasis byidentifying a patient suffering from or at risk of developing psoriasisand administering to the patient a composition that includes Bacilluscoagulans bacteria. The composition is ingested by a human subject thathas one or more symptoms of a dermatological disorder such as psoriasis.Bacterial species include Bacillus coagulans, e.g., Bacillus coagulanshammer, preferably Bacillus coagulans hammer strain Accession No. ATCC31284, or one or more strains derived from Bacillus coagulans hammerstrain Accession No. ATCC 31284 (e.g., ATCC Numbers: GBI-20, ATCCDesignation Number PTA-6085; GBI-30, ATCC Designation Number PTA-6086;and GBI-40, ATCC Designation Number PTA-6087; see U.S. Pat. No.6,849,256 to Farmer). Symptoms of psoriasis include scaling, blistering,skin lesions, itchiness, and pain (e.g., joint pain). In embodiments ofthe invention, the composition also includes a non-microbially derivedantifungal agent (e.g., a member of the azole or pyrrole class ofantifungal compounds such as clotrimazole, fluconazole, itraconazole,ketoconazole, miconazole, nystatin, terbinafine, terconazole, ortioconazole), an immunosuppressive agent (e.g., methotrexate,tacrolimus, cyclosporine, hydroxyurea, mycophenolate mofetil,sulfasalazine, or 6-thioguanine), a retinoid, or an antibiotic agent(e.g., gentamicin, vancomycin, oxacillin, tetracycline, nitroflurantoin,chloramphenicol, clindamycin, trimethoprim sulfamethoxasole, cefaclor,cefadroxil, cefixime, cefprozil, ceftriaxone, cefuroxime, cephalexin,loracarbef, ampicillin, amoxicillin clavulanate, bacampicillin,cloxicillin, penicillin VK, ciprofloxacin, grepafloxacin, levofloxacin,lomefloxacin, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin,azithromycin, or rythromycin). Administration to the patient includesdelivery of the composition(s) via the gastrointestinal tract. Thegastrointestinal tract is the system of organs in a mammal including themouth (buccal cavity), pharynx, esophagus and cardia, stomach(s), andintestines. The bacteria are administered at a dose that reduces a levelof TNF-α in the patient.

Following oral administration, colonization of the gastrointestinaltract with Bacillus coagulans bacteria occurs between 24-48 hours.Continued colonization is improved by the repeated administration ofBacillus coagulans, such as daily administration. For example, aBacillus coagulans bacteria-containing composition is administered(e.g., taken orally) about once every day for about 2, 3, 4, 5, 6, 7,10, 15, 20, 25, 30, 45, 60, 75, 90, 100, 125 or more days. Inembodiments of the invention the Bacillus coagulans bacteria areprovided at a concentration of from about 1×10⁸ to about 1×10¹⁰ viablebacteria, e.g., at a concentration of from about 1×10⁹ to about 2×10⁹viable bacteria. The Bacillus coagulans bacteria are provided in theform of spores and/or vegetative cells.

The invention also provides a method for the treatment of psoriasis byadministering a first dose of a composition containing Bacilluscoagulans bacteria at a first point in time, and administering a seconddose of the composition at a second, subsequent point in time. Thebacteria are, for example, Bacillus coagulans hammer or bacteria derivedfrom Bacillus coagulans hammer strain Accession No. ATCC 31284;available to the public via the ATCC. The treatment includes treating asymptom of psoriasis (e.g., scaling, blistering, skin lesions,itchiness, and joint pain). Bacillus coagulans bacteria are provided ata concentration of from about 1×10⁸ to about 1×10¹° viable bacteria,e.g., at a concentration of from about 1×10⁹ to about 2×10⁹ viablebacteria. The Bacillus coagulans bacteria are provided in the form ofspores or vegetative cells. The composition includes a non-microbiallyderived antifungal agent, such as an azole, an organic five-memberedring compound containing one or more atoms in the ring. Exemplary azolesinclude clotrimazole, fluconazole, itraconazole, ketoconazole,miconazole, nystatin, terbinafine, terconazole, or tioconazole. Theinvention optionally includes administration of an immunosuppressiveagent, such as methotrexate, cyclosporine, hydroxyurea, mycophenolatemofetil, sulfasalazine, or 6-thioguanine, or an antibiotic agent, suchas gentamicin, vancomycin, oxacillin, tetracycline, nitroflurantoin,chloramphenicol, clindamycin, trimethoprim sulfamethoxasole, cefaclor,cefadroxil, cefixime, cefprozil, ceftriaxone, cefuroxime, cephalexin,loracarbef, ampicillin, amoxicillin clavulanate, bacampicillin,cloxicillin, penicillin VK, ciprofloxacin, grepafloxacin, levofloxacin,lomefloxacin, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin,azithromycin, and rythromycin. The bacteria, antifungal compound(s), andimmunosuppressive compound(s) are administered concurrently orsequentially.

The invention also provides a method of reducing a symptom of anautoimmune disorder by identifying a patient suffering from or at riskof developing an autoimmune disorder, and administering to the patient acomposition including Bacillus coagulans bacteria. The autoimmunedisorder is psoriasis, Crohn's Disease, colitis, lupus, arthritis, orany other disorder that is characterized by a pathological increase inactivation of immune cells (e.g., T cells) associated with a pathogenicagent (such as a bacteria, fungus or virus).

The invention further provides a method for decreasing a symptom of anautoimmune disorder in a mammal affected thereby, by administering to amammal a composition that includes Bacillus coagulans bacteria. Asymptom (e.g., scaling, blistering, skin lesions, itchiness, and/orpain) of the autoimmune disorder is decreased following theadministration, compared to the severity of the symptom prior to theadministration.

The invention also provides a method for decreasing serum TNF-α or othercytokine levels in a mammal that has been diagnosed with an elevatedlevel of TNF-α, or one or more other cytokines. Normal human serumlevels of TNFα range from undetectable to about 40 pg/ml of serum, withaverage values in the range of 3-10 pg/ml. TNF-α is preferably detectedby, e.g., ELISA or other quantitative detection means. (Human TNF-αELISA kit, Abazyme, Needham, Mass., or Millenia Diagnostic Product, LosAngeles, Calif.).

Serum cytokine levels (such as TNF-α levels) are decreased following theadministration of Bacillus coagulans, when compared to serum cytokine(such as TNF-α) levels in the mammal prior to the administration.Elevated human serum levels (e.g., greater than about 40, 50, 60, 75,85, 100, 125, 150, 200, 250, 300, or more pg/ml) prior to administrationare associated with autoimmune disorders, and are reduced following acourse of administration of Bacillus coagulans. A reduction in TNF-αlevels confers a clinical benefit to the treated subject, e.g., areduction in a symptom of an autoimmune disorder. The decrease is anymeasurable decrease, such as a decrease greater than about 1%, 5%, 10%,15%, 25%, 50%, 60%, 75%, 85%, 90%, 95%, 99%, 99.9%, 99.99% or greater.The Bacillus coagulans bacteria are provided at a concentration of fromabout 1×10⁸ to about 1×10¹⁰ viable bacteria, such as 5×10⁸, 8×10⁸,1×10⁹, or 5×10⁹ viable bacteria.

The invention further provides a composition that includes a Bacilluscoagulans bacterium, and an immunosuppressive agent. The composition isin the form of a capsule, tablet, powder, or liquid. The Bacilluscoagulans bacteria can be Bacillus coagulans hammer or derived fromBacillus coagulans hammer, e.g., Bacillus coagulans hammer strainAccession No. ATCC 31284.

The invention also provides a system containing medical food for themanagement of psoriasis or other disorder that includes Bacilluscoagulans bacteria, where the medical food is formulated to provide atleast about 1×10⁶ viable Bacillus coagulans bacteria in thegastrointestinal tract of a mammal per day, based on a serving size ofabout 1 gram to about 2 grams of the medical food taken up to abouttwice a day, and instructions for use thereof. In embodiments of theinvention, the medical food optionally includes a non-microbiallyderived anti-fungal agent, an immunosuppressive agent, or anon-microbially derived anti-fungal agent and an immunosuppressiveagent.

Other features and advantages of the invention will be apparent from thefollowing detailed description and from the claims.

DETAILED DESCRIPTION

The mammalian gastrointestinal tract is a complex ecosystem host to adiverse and highly evolved microbial community composed of hundreds ofdifferent microbial species. A perturbation of the interactions thatoccur between this complex microbial community and the mammal can leadto diseases such as illnesses associated with deficient or compromisedmicroflora (e.g., gastrointestinal tract infections, inflammatory boweldiseases (such as Crohn's disease and ulcerative colitis), irritablebowel syndrome, antibiotic-induced diarrhea, constipation, foodallergies, cardiovascular disease, psoriasis, and certain cancers.“Functional food,” e.g., those that contain beneficial bacteria such asBacillus coagulans are useful as therapies to prevent autoimmunediseases and other diseases characterized by an increase in TNF-αcompared to normal, control levels.

Lactic acid bacteria (LAB) display numerous health benefits beyondproviding general digestive value. They cooperatively maintain aphysiological balance between the gastrointestinal tract and immunesystem. When this balance is disrupted, disease and inflammation oftenresult. Deleterious bacteria are competitively inhibited by the mucosaladherence or transient colonization of beneficial microflora such asBacillus coagulans. A healthy gastrointestinal tract with adequate mucusproduction and appropriate bacterial colonization prevents or inhibitsthe growth of pathogenic or opportunistic microorganisms, modulatesdisease processes, and prevents widespread inflammatory disorders.

Bacillus coagulans is an L+ lactic acid-producing bacterium that hasbeen shown to be highly effective in the colonization of the variousmucosal surfaces of the gastrointestinal tract. Unlike strictlyvegetative species of lactic acid bacteria (e.g., Lactobacillus,Bifidobacterium, and other bacteria) that are used in therapeuticapplications, Bacillus coagulans survives intact after exposure toextremely low pH of stomach and bile acids. This is accomplished due tothe extremophile nature of the vegetative form of this organism(thermo-tolerant, acidophilic, baro-tolerant, and halo-tolerant), andthat it forms endospores. In addition, Bacillus coagulans is highlycompetitive, which is an important feature for the high-densitycolonization that is required to promote physiological changes in thesmall and large bowel. Further, Bacillus coagulans has been shown inMinimum Inhibitory Concentration (MIC) dilution (in vitro) studies toinhibit many enteric bacterial pathogens (Escherichia, Proteus,Clostridium, Campylobacter, Shigella, Salmonella, Enterococcus,Staphylococcus, Streptococcus, and others), which require a higher thanneutral pH in order to proliferate. MIC studies have also been performedthat indicate high inhibitory activity on various mycotic pathogenschallenged with Bacillus coagulans.

The methods and compositions of the present invention are useful in thetreatment of autoimmune diseases. Autoimmune diseases can affect almostany organ or tissue of the body, and are thus amenable to classificationby the affected tissue(s). It is recognized that an autoimmune diseaseor disorder can impact one or more tissues. Autoimmune disorders thataffect the blood or vasculature including autoimmune hemolytic anemia,pernicious anemia, polyarteritis nodosa, systemic lupus erythematosus,and Wegener's granulomatosis. Autoimmune disorders of thegastrointestinal system include autoimmune hepatitis, Behçet's disease,Crohn's disease, primary biliary cirrhosis, scleroderma, ulcerativecolitis, and Irritable Bowel Syndrome (IBS). Autoimmune disorders thataffect the ocular system include Sjögren's syndrome, type 1 diabetesmellitus, and uveitis. Autoimmune disorders that affect the endocrinesystem include Graves' disease, and thyroiditis. Autoimmune disordersthat affect the cardiovascular system include myocarditis, rheumaticfever, scleroderma, and systemic lupus erythematosus. Autoimmunedisorders that affect connective tissue include ankylosing spondylitis,rheumatoid and reactive arthritis, and systemic lupus erythematosus. Anautoimmune disorder that affects the kidneys is glomerulonephritis. Anautoimmune disorder that affects the lungs is glomerulonephritis issarcoidosis. Autoimmune disorders that affect the musculoskeletal systeminclude dermatomyositis, myasthenia gravis, polymyositis, andfibromialgia. Autoimmune disorders that affect the neurological systeminclude Guillain-Barré syndrome, and multiple sclerosis. Autoimmunedisorders that affect the skin include alopecia areata, pemphigus (alsotermed pemphigoids), psoriasis, and vitiligo.

Symptoms of autoimmune disease include fatigue, dizziness, malaise,fever, and decreased platelet and/or eosinophil counts. Further, certainautoimmune diseases are characterized by destruction of a type of tissue(e.g., destruction of islet cells of the pancreas in diabetes) or theincrease in organ size (e.g., thyroid enlargement in Graves Disease).For treatment or prevention of such diseases or conditions and reductionof symptoms associated with these conditions, compositions that containBacillus coagulans bacteria are administered according to the methodsdescribed herein.

TNF-α is a naturally occurring cytokine, which is produced by activatedimmune cells. However, excessive activation of immune effector cells andoverproduction of TNF-α can cause severe inflammation and tissue damage.TNF-α plays a major role in a number of disease states, e.g., psoriasis,Crohn's disease, rheumatoid arthritis, ulcerative colitis, andankylosing spondylitis. Reducing the level of TNF-α in patientssuffering from or at risk of developing autoimmune disease orinflammatory disease states alleviates symptoms of the disease andprevents or slows disease progression.

Reducing TNF-α by administering Bacillus coagulans confers a clinicalbenefit (e.g., reduced inflammation) with little or none of the sideeffects associated with other, non-microbial TNF-α inhibitors (e.g.,infliximab, etanercept, and adalimumab). Administration of Bacilluscoagulans confers a clinical benefit to subjects identified as sufferingfrom or at risk of developing the following exemplary autoimmunedisorders.

Psoriasis

Psoriasis is a skin disease that is characterized in part by abnormalproliferation and differentiation of keratinocytes, T-cell andendothelial cell activation, local vascular changes, and neutrophilaccumulation as well as other immunological processes, e.g., alteredlevels of cytokines. Results of cyclosporine and fluconazole treatmentsalso demonstrate that bacterial and mycotic agents play a significantrole in psoriasis.

Psoriasis generally results from a genetic defect in combination withexternal triggers that affect the features of the disease. The cellularimmune system plays a dominant role in exacerbation of psoriasis.Microorganisms such as β-hemolytic streptococci, Staphylococcus aureusand Candida albicans are external triggers that release factors whichserve as superantigens, and stimulate the T cells to initiate psoriasis,which often resulting in a “pathogenic circle” of repeated incidences ofthe disease. The source of the microorganisms may be in the skin itselfor in distal locations, such as Streptococcus in the throat or Candidaalbicans in the gut. From these locations, the microorganisms cause therelease of superantigens that travel through the host's vascular systemto reach the skin and initiate the psoriatic process.

There are many different forms of psoriasis, including plaque psoriasis(vulgaris psoriasis), guttate psoriasis, pustular psoriasis,erythrodermic psoriasis, nail psoriasis, scalp psoriasis, inversepsoriasis, and psoriatic arthritis. Symptoms of psoriasis vary among theforms of psoriasis, and between affected individuals. As used herein, a“symptom” of psoriasis includes any observable, measurable or detectablesign or indication of any form of psoriasis or a psoriasis-relatedcondition. A patient suffering from psoriasis has one or more symptomsof psoriasis. Psoriasis symptoms include scaling, blistering, skinlesions, itchiness, and joint pain. Other symptoms of psoriasis areknown to those of ordinary skill in the art. Psoriasis is diagnosed bythe observation or detection of one or more symptoms of psoriasis.Generally, a patient suffering from or at risk of developing psoriasishas one or more symptoms of psoriasis, or a family member havingpsoriasis or a symptom of psoriasis.

Indications of treatment of psoriasis include any detectable change(e.g., a decrease or disappearance) in a symptom of psoriasis, asmeasured by size, severity, duration, or the presence or absence ofrelapses of affected skin. A preferred method of determining theefficacy of a treatment is the measurement of the change in the totalpsoriatic lesion area following Bacillus coagulans treatment, ascompared to the in total psoriatic lesion area prior to treatment. Also,a measurable decrease in the amount of serum TNF-α in a patientundergoing psoriasis treatment indicates the efficacy of the treatment.Further, the efficacy of treatment can be determined by the decrease inpathogenic microorganisms present in the gastrointestinal tract of thepatient undergoing treatment, such as by measuring the presence of thesemicroorganisms in stool measurement in stool or other biologicalmaterials.

Inflammatory Bowel Disease

Human inflammatory bowel disease (IBD) is a group of intestinalinflammatory diseases that can be subdivided in ulcerative colitis (UC)and Crohn's disease (CD) based on typical clinical manifestations. Thesymptoms of both are extremely unpleasant and impact all aspects ofquality of life. They include diarrhea, abdominal pain, rectal bleeding,fever, nausea, weight loss, lethargy and loss of appetite. If leftuntreated, malnutrition, dehydration and anemia follow, which, inextreme cases, lead to death. Although UC and CD show a considerabledegree of similarity in etiology and epidemiology, they are entirelydifferent in pathology. UC is restricted to the colon. CD, however, hasbeen observed throughout the entire intestinal tract, from the mouth tothe rectum. Inflammation is restricted to the mucosa in UC, whereas inCD the inflammation can be transmural, i.e., penetrating the bowel wall.This often leads to the development of perianal fistulae. An imbalancein T-helper (Th) subsets of T cells, so called Th1 and Th2,differentiates CD from UC on an immunological basis. In UC, anover-expression of Th2 type cytokines (IL-4, IL-5) has beendemonstrated, whereas in CD, Th1 type cytokines (IL-12, IFN-γ)predominate.

CD and UC involve an interaction between genetic and environmentalfactors, such as bacterial agents. Abnormal immune responses, driven bythe intestinal microflora, occur in IBD. Most experimental models forIBD cannot be established in germ-free animals. In one art-recognizedexperimental model, IL-10−/− mice show that the appearance of mucosaladherent colonic bacteria is causative of the development andmaintenance of the inflammation.

Breach of tolerance towards normal intestinal microflora may thus be thedriving force behind IBD. The absence of tolerance to the indigenousmicroflora also appears in trinitrobenzene sulphonic acid (TNBS)-inducedcolitis. The administration of IL-10, a central mediator indown-regulation of immune reactions, restores healthy status byreestablishing tolerance. This treatment does not, however, affectimmune reactivity towards heterologous bacterial antigen. Staphylococcalenterotoxin B can abrogate self-tolerance at the intestinal epithelium.IL-10 can counteract this by preventing the activation of T cells thatcontribute to epithelial cell damage. T-cell clones stimulated byindigenous aerobic flora and bifidobacteria were also identified inpatients with IBD.

Higher bacterial load has been reported in the mucus of IBD patients.Although a number of reports measure no significant differences in theflora composition of UC patients when compared with controls, two recentstudies indicate significant decrease of lactobacilli in UC. There areconflicting reports on the composition of the microflora in CD althoughit is difficult to compare disease stages when assessed in differentcenters. Bifidobacterium species are found to be decreased in CD. Asignificant increase in Escherichia coli and Bacteroides fragilis wasdetected in the ileum and of E. coli and lactobacilli in the colon,although lactobacilli, together with bifidobacterial scores, have alsobeen found significantly reduced in CD patients.

The development of IBD is in some cases linked to viral or bacterialinfection (Mycobacteria, Shigella, Salmonella, Yersinia, Clostridiumdifficile, Bacteroides vulgatus) but to date no etiological agent hasbeen identified for IBD. Recently, however, a DNA sequence has beenidentified in lamina propria mononuclear cells of which the presence andserum reactivity towards the according peptide highly correlates withCD. This presently unknown sequence is not of human origin and showshomology with bacterial tetR/acrR transcription regulators.

Systemnic Lupus Erythematosus (SLE)

An inflammation of the connective tissues, SLE impacts one or moreorgans or tissues in a subject. It is up to nine times more common inwomen than men. Further, SLE impacts black women three times as often asCaucasian women. The condition is aggravated by sunlight. Symptomsinclude fever, weight loss, hair loss, mouth and nose sores, malaise,fatigue, seizures and symptoms of mental illness. Identification of apatient suffering SLE from is accomplished by identifying one or more ofthese symptoms in the patient. Ninety percent of patients experiencejoint inflammation similar to rheumatoid arthritis. Fifty percentdevelop a classic “butterfly” rash on the nose and cheeks. Raynaud'sphenomenon (extreme sensitivity to cold in the hands and feet) appearsin about 20 percent of people with SLE. Current treatments are limitedto the use of anti-inflammatory drugs to control arthritis symptoms, andtopical steroidal creams to treat skin lesions, while oral steroids,such as prednisone, are used for the systemic symptoms. One or moresymptoms of SLE are reduced following treatment with Bacillus coagulansbacteria.

Rheumatoid Arthritis

Rheumatoid arthritis is a systemic disorder in which immune cells attackand inflame the membrane around joints. It also can affect the heart,lungs, and eyes. Of the estimated 2.1 million Americans with rheumatoidarthritis, approximately 1.5 million (71 percent) are women. Symptoms ofthe disease include inflamed and/or deformed joints, loss of strength,swelling, and pain. Identification of a patient suffering fromrheumatoid arthritis is accomplished by identifying one or more of thesesymptoms in the patient. Current treatment modalities include rest andanti-inflammatory drugs. One or more symptoms of rheumatoid arthritisare reduced following treatment with Bacillus coagulans bacteria.

Scleroderma (Systemic Sclerosis)

Scleroderma involves the hyperactivity of certain immune cells, whichproduce fibrous, scar-like tissue in the skin, internal organs, andsmall blood vessels. It affects women three times more often than menoverall, but increases to a rate 15 times greater for women duringchildbearing years, and appears to be more common among black women thanCaucasian women. Symptoms of scleroderma include the appearance ofRaynaud's phenomenon, as well as swelling and puffiness of the fingersor hands. Often, skin thickening follows, and other symptoms includeskin ulcers on the fingers, joint stiffness in the hands, pain, sorethroat, and diarrhea. Identification of a patient suffering fromscleroderma is accomplished by identifying one or more of these symptomsin the patient. Current treatments of scleroderma includeD-penicillamine, which has been shown to decrease skin thickening. Thisdisorder also impacts other organs such as the kidneys, esophagus,intestines, and blood vessels and thus requires multi-system treatments.One or more symptoms of scleroderma are reduced following treatment withBacillus coagulans bacteria.

Sjogren's Syndrome

Sjögren's syndrome (also called Sjögren's disease) is a chronic, slowlyprogressing inability to secrete saliva or tears. It can occur alone orwith rheumatoid arthritis, scleroderma, or systemic lupus erythematosus.Nine out of 10 cases occur in women, most often at or around mid-life.Symptoms of this disorder include dryness of the eyes and mouth, swollenneck glands, difficulty swallowing or talking, unusual tastes or smells,thirst, tongue ulcers, or severe dental caries. Identification of apatient suffering from Sjögren's syndrome is accomplished by identifyingone or more of these symptoms in the patient. Current treatments includeinterventions to keep the mouth and eyes moist (including drinking a lotof fluids and using eye drops, as well as good oral hygiene and eyecare). One or more symptoms of Sjögren's syndrome are reduced followingtreatment with Bacillus coagulans bacteria.

Multiple Sclerosis (MS)

Multiple sclerosis is a disease of the central nervous system thatusually first appears between the ages of 20 and 40; it affects womentwice as often as men. MS is the leading cause of disability among youngadults. MS is recognized to be an unpredictable disease of the centralnervous system, and can range from relatively benign to somewhatdisabling to devastating, as communication between the brain and otherparts of the body is disrupted. Symptoms of MS include fatigue, problemswalking, bowel and/or bladder disturbances, visual problems, changes incognitive function, including problems with memory, attention, andproblem-solving, abnormal sensations such as numbness or “pins andneedles,” changes in sexual function, pain, depression and/or moodswings, tremor, speech and swallowing problems, and impaired hearing.Identification of a patient suffering from multiple sclerosis isaccomplished by identifying one or more of these symptoms in thepatient. The vast majority of patients are mildly affected, but in theworst cases MS can render a person unable to write, speak, or walk. Oneor more symptoms of MS are reduced following treatment with Bacilluscoagulans bacteria.

Myasthenia Gravis

Myasthenia gravis is a chronic autoimmune disorder characterized bygradual muscle weakness, often appearing first in the subject's face andoften characterized by drooping eyelids, as well as double vision,difficulty breathing, talking, chewing, and swallowing. Identificationof a patient suffering from myasthenia gravis is accomplished byidentifying one or more of these symptoms in the patient. The drugedrophonium is currently used as a treatment, along with daily restperiods, which can improve muscle strength. One or more symptoms ofmyasthenia gravis are reduced following treatment with Bacilluscoagulans bacteria.

Guillain-Barre Syndrome

Guillain-Barré syndrome is a disorder in which the body's immune systemattacks part of the peripheral nervous system. The first symptoms ofthis disorder include varying degrees of weakness or tingling sensationsin the legs. Identification of a patient suffering from Guillain-Barrésyndrome is accomplished by identifying one or more of these symptoms inthe patient. In many instances, the weakness and abnormal sensationsspread to the arms and upper body. These symptoms can increase inintensity until the muscles cannot be used at all and the patient isalmost totally paralyzed. In these cases, the disorder is lifethreatening and is considered a medical emergency. The patient is oftenput on a respirator to assist with breathing. Most patients, however,recover from even the most severe cases of Guillain-Barré syndrome,although some continue to have some degree of weakness. Guillain-Barrésyndrome is rare. Usually Guillain-Barré occurs a few days or weeksafter the patient has had symptoms of a respiratory or gastrointestinalviral infection. Occasionally, surgery or vaccinations will trigger thesyndrome. The disorder can develop over the course of hours or days, orit may take up to 3 to 4 weeks. Because the signals traveling along thenerve are slower, a nerve conduction velocity (NCV) test is used to aiddiagnosis. Increased protein in the cerebrospinal fluid is also used todiagnose Guillain-Barré syndrome. One or more symptoms of Guillain-Barrésyndrome are reduced following treatment with Bacillus coagulansbacteria.

Hashimoto's Thryroiditis

Hashimoto's thyroiditis is a type of autoimmune disease in which theimmune system destroys the thyroid, the gland that helps set the rate ofmetabolism. It attacks women 50 times more often than men. Symptoms ofthis disorder include low levels of thyroid hormone, resulting in mentaland physical slowing, greater sensitivity to cold, weight gain,coarsening of the skin, and goiter (a swelling of the neck due to anenlarged thyroid gland). Identification of a patient suffering fromHashimoto's thyroiditis is accomplished by identifying one or more ofthese symptoms in the patient. Currently, thyroid hormone replacementtherapy is used to treat this disorder. One or more symptoms ofHashimoto's thyroiditis are reduced following treatment with Bacilluscoagulans bacteria.

Graves' Disease

Graves' disease is one of the most common autoimmune diseases, andimpacts women about seven times as often as men. Subjects with Graves'disease produce an excessive amount of thyroid hormone. Symptoms ofGraves' disease include weight loss due to increased energy expenditure,increased appetite, heart rate, and blood pressure, tremors, nervousnessand sweating, as well as frequent bowel movements. Identification of apatient suffering from Graves' disease is accomplished by identifyingone or more of these symptoms in the patient. Treatment options includeanti-thyroid drug therapy or removal of the thyroid gland, e.g.,surgically or by radioiodine treatment. One or more symptoms of Graves'disease are reduced following treatment with Bacillus coagulansbacteria.

Insulin-Dependent (Type 1) Diabetes

Type 1 diabetes is caused by too little insulin production in thepancreas, and usually occurs in children and young adults, but it canoccur at any age. Symptoms include increased thirst, increasedurination, weight loss, fatigue, nausea, vomiting, and frequentinfections. Identification of a patient suffering from diabetes isaccomplished by identifying one or more of these symptoms in thepatient. Insulin treatment is the current treatment modality. One ormore symptoms of diabetes are reduced following treatment with Bacilluscoagulans bacteria.

Inflammatory Bowel Disease

Crohn's disease (also called ileitis or enteritis) causes inflammationin the small intestine. Crohn's disease usually occurs in the lower partof the small intestine, called the ileum, but it can affect any part ofthe digestive tract, from the mouth to the anus. The inflammationextends deep into the lining of the affected organ. The inflammation cancause pain and can make the intestines empty frequently, resulting indiarrhea. Identification of a patient suffering from Crohn's disease isaccomplished by identifying one or more of these symptoms in thepatient. Crohn's disease is one form of inflammatory bowel disease.Crohn's disease can be difficult to diagnose because its symptoms aresimilar to other intestinal disorders such as irritable bowel syndromeand to another type of IBD called ulcerative colitis. Ulcerative colitiscauses inflammation and ulcers in the top layer of the lining of thelarge intestine. Crohn's disease affects men and women equally and seemsto run in some families. About 20 percent of people with Crohn's diseasehave a blood relative with some form of IBD, most often a brother orsister and sometimes a parent or child. One or more symptoms of Crohn'sdisease are reduced following treatment with Bacillus coagulansbacteria.

Ulcerative Colitis

Ulcerative colitis is a disease that causes inflammation and sores,called ulcers, in the lining of the large intestine. The inflammationusually occurs in the rectum and lower part of the colon, but it mayaffect the entire colon. Ulcerative colitis rarely affects the smallintestine except for the end section, called the terminal ileum.Ulcerative colitis may also be called colitis or proctitis. Symptoms ofUC include fatigue, weight loss, loss of appetite, rectal bleeding andloss of body fluids and nutrients. Identification of a patient sufferingfrom UC is accomplished by identifying one or more of these symptoms inthe patient. The inflammation makes the colon empty frequently, causingdiarrhea. Ulcers form in places where the inflammation has killed thecells lining the colon; the ulcers bleed and produce pus. Crohn'sdisease differs from ulcerative colitis because it causes inflammationdeeper within the intestinal wall. Also, Crohn's disease usually occursin the small intestine, although it can also occur in the mouth,esophagus, stomach, duodenum, large intestine, appendix, and anus.Ulcerative colitis may occur in people of any age, but most often itstarts between ages 15 and 30, or less frequently between ages 50 and70. Children and adolescents sometimes develop the disease. Ulcerativecolitis affects men and women equally and appears to run in somefamilies. One or more symptoms of UC are reduced following treatmentwith Bacillus coagulans bacteria.

Celiac Disease

Celiac disease is a digestive disease that damages the small intestineand interferes with absorption of nutrients from food. Subjects withceliac disease cannot tolerate a protein called gluten, which is foundin wheat, rye, and barley. When people with celiac disease eat foodscontaining gluten, their immune system responds by damaging the smallintestine. Specifically, the intestinal villi are lost, resulting inmalnutrition. Symptoms of Celiac disease include diarrhea, abdominalpain and bloating, gas, irritability, depression, weight loss, delayedgrowth, failure to thrive in infants, anemia, and fatigue.Identification of a patient suffering from Celiac disease isaccomplished by identifying one or more of these symptoms in thepatient. Celiac disease is also known as celiac sprue, nontropicalsprue, and gluten-sensitive enteropathy. Celiac disease may be inducedfollowing surgery, pregnancy, childbirth, viral infection, or severeemotional stress. One or more symptoms of Celiac disease are reducedfollowing treatment with Bacillus coagulans bacteria.

Vasculitis Syndromes

This is a broad and heterogeneous group of diseases characterized bysymptoms including inflammation and damage to the blood vessels, thoughtto be brought on by an autoimmune response. Identification of a patientsuffering from vasculitis is accomplished by identifying one or more ofthese symptoms in the patient. Any type, size, and location of bloodvessel may be involved. Vasculitis may occur alone or in combinationwith other diseases, and may be confined to one organ or involve severalorgan systems. One or more symptoms of vasculitis are reduced followingtreatment with Bacillus coagulans bacteria.

Hematologic Autoimmune Diseases

Blood also can be affected by an autoimmune disorder. In autoimmunehemolytic anemia, red blood cells are prematurely destroyed byantibodies. Other autoimmune diseases of the blood include autoimmunethrombocytopenic purpura and autoimmune neutropenia. One or moresymptoms of these blood disorders are reduced following treatment withBacillus coagulans bacteria.

The present inventors recognize that certain autoimmune disorders affectprimarily women, as noted for several autoimmune disorders describedabove. The present invention discloses the prevention or treatment of anautoimmune disorder in a female subject. In embodiments of theinvention, the autoimmune disorder to be treated or prevented in afemale patient is Hashimoto's disease (also known as hypothyroiditis),systemic lupus erythematosus, Sjogren's syndrome, antiphospholipidsyndrome, primary biliary cirrhosis, mixed connective tissue disease,chronic active hepatitis, Graves' disease (also termedhyperthyroiditis), rheumatoid arthritis, scleroderma, myasthenia gravis,multiple sclerosis, or chronic idiopathic thrombocytopenic purpura.

Bacillus coagulans Therapy Reduces Gastrointestinal Infection byAutoimmune Disease-Associated Pathogenic Microorganisms

Many species of bacterial, mycotic and yeast pathogens possess theability to cause a variety of disorders, including autoimmune disorders.Bacillus coagulans, a probiotic microorganism is useful in theprophylactic or therapeutic treatment of autoimmune conditions such aspsoriasis, which are associated with infection by these aforementionedpathogens. Generally, Bacillus coagulans bacteria (i) possess theability to produce and excrete enzymes useful in digestion (e.g.,lactase, various proteases, lipases and amylases); (ii) demonstratebeneficial function within the gastrointestinal tract; (iii) serve todown-regulate the cytokine response as a result of bacterial/fungal/ormycotic interaction with the various mucosal cells; and (vi) arenon-pathogenic. Bacillus coagulans bacteria are able to inhibitpathogenic yeast and other fungi, including Candida albicans, Candidatropicalis and Trichophyton mentagrophytes, Trichophyton interdigitale,Trichophyton rubrum, and Trichophyton yaoundei. Bacillus coagulansbacteria are also able to inhibit pathogenic bacteria, includingStaphylococcus species, Streptococcuspyogenes species, Pseudomonasspecies, Escherichia coli, Clostridium species, Gardnereia vaginailis,Proponbacterium acnes, Aeromonas species, Aspergillus species; Proteusspecies; and Klebsiella species.

Strains of Bacillus coagulans bacteria are available from the AmericanType Culture Collection (ATCC), including the following accessionnumbers: Bacillus coagulans Hammer NRS 727 (ATCC No. 11014); Bacilluscoagulans Hammer strain C (ATCC No. 11369); Bacillus coagulans Hammer(ATCC No. 31284); Bacillus coagulans Hammer NCA 4259 (ATCC No. 15949);and strains deposited under ATCC Accession Numbers 8038, 35670, 23498,51232, 12245, 10545 and 7050. Purified Bacillus coagulans bacteria arealso available from the Deutsche Sarumlung von Mikroorganismen undZellkuturen GmbH (Braunschweig, Germany) using the following accessionnumbers: Bacillus coagulans Hammer 1915 (DSM No. 2356); Bacilluscoagulans Hammer 1915 (DSM No. 2383, corresponds to ATCC No. 11014);Bacillus coagulans Hammer (DSM No. 2384, corresponds to ATCC No. 11369);and Bacillus coagulans Hammer (DSM No. 2385, corresponds to ATCC No.15949). Bacillus coagulans bacteria can also be obtained from commercialsuppliers such as K. K. Fermentation (Kyoto, Japan) and NebraskaCultures (Walnut Creek, Calif.).

The Bacillus coagulans bacterial strain used to reduce infection bymicrobial pathogens is Bacillus coagulans hammer, or a strain derivedtherefrom. For example, the Bacillus coagulans bacterial strain is ATCC31284, or a strain derived therefrom. These strains include, e.g., ATCCNumbers GBI-20, ATCC Designation Number PTA-6085, available to thepublic via the ATCC; GBI-30, ATCC Designation Number PTA-6086, availableto the public via the ATCC; and GBI-40, ATCC Designation NumberPTA-6087, available to the public via the ATCC; see U.S. Pat. No.6,849,256 to Farmer, the contents of which are incorporated by referencein their entirety.

A composition comprising Bacillus coagulans bacteria in apharmaceutically acceptable carrier suitable for oral administration tothe gastrointestinal tract of a mammal (e.g., a human) animal isdisclosed. Bacillus coagulans bacteria are provided in amountssufficient to colonize the gastrointestinal tract of a mammal. Theinvention provides Bacillus coagulans bacteria at a concentration offrom about 1×10⁴ to about 1×10¹² viable bacteria, specifically about1×10⁶ to about 1×10¹¹, more specifically about 1×10⁸ to about 1×10¹⁰,and most specifically about 8×10⁸ . Bacillus coagulans bacteria areprovided as vegetative cells, spores, or a combination thereof.

Vegetative cells are formulated in a composition that protects the cellsfrom being killed by the acid environment of the stomach. Cellsformulated in this manner successfully traverse the stomach to colonizethe small and/or large intestine. Accordingly, the invention includes acomposition containing a Bacillus coagulans bacterium in apharmaceutically acceptable acid-resistant (“enteric”) carrier. Byacid-resistant is meant that the carrier or coating does not dissolve inan acidic environment. An acidic environment is characterized by a pH ofless than 7. The acid-resistant carrier is resistant to acids at pH lessthan about 4.0. Preferably, the carrier does not dissolve in pH 2-3.Most preferably, it does not dissolve in pH of less than 2. To protectvegetative bacterial cells from stomach acids, the cells are coated orencapsulated with the acid-resistant carrier. The composition optionallyincludes other components such as glucose and phosphoric acid or othernutrient compounds to increase bacterial growth after removal of thecarrier or coating. The invention also includes Bacillus coagulansbacteria in the form of spores, which are selected for the capability ofgerminating in the presence of bile acids such as cholic, deoxycholicand tauro-deoxycholic acids. Enterically coated and bile acid-resistantBacillus coagulans bacteria are described in U.S. Ser. No. 10/287,904,filed Nov. 5, 2002, the contents of which are incorporated by referencein their entirety.

The compositions contain Bacillus coagulans bacteria and one or morebiologically active compounds; such as a natural or synthetic compoundthat decreases or relieves a symptom of psoriasis. Exemplary compoundsinclude immunosuppressants including methotrexate, cyclosporine,hydroxyurea, mycophenolate mofetil, sulfasalazine, 6-thioguanine, andother compounds such as retinoids.

Example 1 Preparation of Bacillus coagulans Bacteria

I. Preparation of Vegetative Bacillus coagulans

Bacillus coagulans is aerobic and facultative, and is typically culturedat pH 5.7 to 6.8, in a nutrient broth containing up to 2% (by wt) NaCl,although neither NaCl, nor KCl are required for growth. A pH of about4.0 to about 7.5 is optimum for initiation of sporulation (i.e., theformation of spores). The bacteria are optimally grown at 20° C. to 45°C., and the spores can withstand pasteurization. Additionally, thebacteria exhibit facultative and heterotrophic growth by utilizing anitrate or sulfate source. Bacillus coagulans strains and their growthrequirements have been described previously (see e.g., Baker, D. et al,1960. Can. J Microbiol. 6: 557-563; Nakamura, H. et al, 1988. Int. J.Syst. Bacteriol. 38: 63-73. In addition, various strains of Bacilluscoagulans can also be isolated from natural sources (e.g., heat-treatedsoil samples) using well-known procedures (see e.g., Bergey's Manual ofSystemic Bacteriology, Vol. 2, p. 1117, Sneath, P. H. A. et al., eds.Williams & Wilkins, Baltimore, Md., 1986).

Bacillus coagulans bacteria are cultured in a variety of media, althoughit has been demonstrated that certain growth conditions are moreefficacious at producing a culture that yields a high level ofsporulation. For example, sporulation enhanced by supplementing theculture medium with 10 mg/l of MgSO₄ sulfate, yielding a ratio of sporesto vegetative cells of approximately 80:20. In addition, certain cultureconditions produce a bacterial spore that contains a spectrum ofmetabolic enzymes particularly suited for the present invention (i.e.,production of lactic acid and enzymes for the enhanced probioticactivity and biodegradation). Although the spores produced by theseaforementioned culture conditions are preferred, various othercompatible culture conditions that produce viable Bacillus coagulansspores are utilized in the practice of the present invention.

Suitable media for the culture of Bacillus coagulans include: TSB(Tryptic Soy Broth), GYE (Glucose Yeast Extract Broth), and NB (nutrientbroth), which are all well known within the field and available from avariety of sources. Media supplements which contain enzymatic digests ofpoultry and/or fish tissue, and containing food yeast are particularlypreferred. A preferred supplement produces a media containing at least60% protein, and about 20% complex carbohydrates and 6% lipids. Mediacan be obtained from a variety of commercial sources, notably DIFCO(Newark, N.J.); BBL (Cockeyesville, Md.); and Troy Biologicals (Troy,Md.)

II. Preparation of Bacillus coagulans Spores

A culture of dried Bacillus coagulans Hammer bacteria (ATCC No. 31284)spores was prepared as follows. Approximately 1×10⁷ spores wereinoculated into one liter of culture medium containing: 30 g (wt./vol.)Tryptic Soy Broth; 10 g of an enzymatic-digest of poultry and fishtissue; and 10 g MnSO₄. The culture was maintained for 72 hours under ahigh oxygen environment at 37° C. so as to produce a culture havingapproximately 6×10⁹ cells/gram of culture. The culture was thencentrifuged to remove the liquid culture medium and the resultingbacterial paste was re-suspended in 100 ml of sterile water and 20%malto-dextrin and lyophilized. The lyophilized bacteria were ground to afine powder by use of standard good manufacturing practice (GMP)methodologies.

Example 2 Formulations and Administration

Vegetative bacterial cells and spores are administered at a dose of10,000−10¹¹ cells per administration. A typical therapeutic compositionof the present invention contains in a one-gram dosage formulation, fromapproximately 1×10³ to 1×10¹², and preferably approximately 2×10⁵ to2×10¹⁰, colony-forming units (CFU) of viable Bacillus bacteria (i.e.,vegetative bacteria) or bacterial spores. Typically, Bacillus coagulansbacteria remain in and colonize the colon for a period of 3-5 dayspost-administration.

Formulation #1 Bacillus coagulans 8.0 × 10⁸ (53 mg) Saccharomycesboulardii 1.5 × 10⁸ (7.5 mg) Copper Sulfate 5 mcg Vitamin C 50 mgSelenium 2.5 mcg Micro-Crystalline Cellulose 132 mg Total 250 mgFormulation #2 Bacillus coagulans 8.0 × 10⁸ (53 mg) Saccharomycesboulardii 1.5 × 10⁸ (7.5 mg) L-Lysine 75 mg Maltodextrin 35 mg Blue lake#1 Dye 1 mg Aspartame 2 mg Compressible Sugars 173 mg Total 350 mgFormulation #3 Bacillus coagulans 1.5 × 10⁹ (100 mg) Maltodextrin 35 mgMicrocrystalline Cellulose 140 mg Total 350 mg Formulation #4 Bacilluscoagulans 1.5 × 10⁹ (100 mg) Sarccharomyces boulardii 2.5 × 10⁸ (12.5mg) L-Lysine 75 mg Microcrystalline Cellulose 163 mg Total 350 mgFormulation #5 Bacillus coagulans 1.5 × 10⁹ (100 mg) L-Lysine 75 mgFluconazole 2% 150 mg Filler 25 mg Total 350 mg

The invention provides for the addition of other useful ingredients.Many individuals that suffer from immune disorders of this nature alsohave been shown to have vitamin and mineral deficiencies. Hence,addition of vitamin and mineral supplements is useful for the dietarymanagement of these disorders.

Example 3 Use of Bacillus coagulans Bacteria in the Treatment andClinical Remission of Chronic Psoriasis

Probiotic bacteria reduce the numbers of pathogens in the gut of humansand animals. In addition, Bacillus coagulans bacteria downregulate thebody's cytokine response to toxins and pathogenic organisms.

A number of deleterious microorganisms promote over-stimulation ofimmune system. In the case of psoriasis, this leads to the production ofcytokines (TNF-a) that cause the formation of dermal plates. Candidaalbicans is the underlying infection in these circumstances. It iscommon for physicians today to prescribe systemic antifungal compoundsto reduce psoriatic lesions. Unfortunately, the antifungal most oftenused in these circumstances is Fluconazole, which can only be used for30 days (as per FDA guidelines). With these issues in mind, studies werecarried out to determine whether Bacillus coagulans lactic acid bacteriacould be employed to reduce the number of Candida species in the stoolwhile down regulating the production of TNF-a as a result of the Candidainfection.

Twelve human patients with chronic psoriasis were studied at a Generalpractice clinic in Cleveland, Ohio over a three-month period. Patientswere provided with capsules containing Bacillus coagulans bacteria(7.5×10⁸ colony forming units (CFU)) and microcrystalline cellulose as acarrier, and instructed to take two capsules per day. There were norestrictions on the time of day of consumption or if the two capsuleswere taken at the same or different times during the day. The treatmentlasted three months; patients were observed at the beginning and end ofthe treatment.

Results after a two-month period indicated that Bacillus coagulanstherapy was nearly 100% effective in reducing the surface area ofpsoriatic plates in patients suffering from Psoriasis vulgaris. Thephysician that conducted the study did not that a few younger patients(16-25 years of age) that had plates over >60% of their respectivebodies did show results much quicker than the patients that were older(50 years of age or older), and had been affected by the disease for amuch longer period (>20 years). Five patients that showed excellentresults after therapy discontinued use of the formulation (for variousreasons) and their psoriatic plates returned very quickly. Afterre-initiating therapy, the plates started to recede again. Thisindicates that the underlying Candida infection may not be totallyeliminated and that a longer period of therapy may be required tomaintain the results. Moreover, some individuals are more susceptible tomycotic infection and as a result, these individuals need to manage thisstate with continued use of the formulation. The usage parameters may bedifferent for dietary management after initial results but, to guaranteethat the initial results are maintained, the a minimum of one capsule aday ongoing may be sufficient.

Example 4 Use of Bacillus coagulans Bacteria to Reduce Serum TNF-αLevels

Colonization of the mammalian gastrointestinal tract by pathogenicmicroorganisms leads to the aberrant production of cytokines (e.g.,TNF-α), which cause symptoms of psoriasis, such as dermal plates. Oraladministration of Bacillus coagulans bacteria is examined for theability to decrease cytokine production in human subjects suffering fromor at risk of developing psoriasis.

Materials and Methods

Subjects are identified by the presence or past incidence of one or moresymptoms of psoriasis, or by a family history of the disease (one ormore parents, grandparents or siblings having one or more symptoms ofpsoriasis). Non-affected individuals are used as controls. Serumcytokine levels are determined prior to Bacillus coagulans bacteriatreatment, at regular intervals throughout the duration of thetreatment, and upon completion of the treatment. Measured cytokinesinclude TNF-α and interleukin-6 (IL-6). Measurement of serum cytokinelevels is performed by methods known in the art, such as ELISA. Bacilluscoagulans bacteria are administered to affected and non-affectedsubjects such that at least about 1×10⁶ viable Bacillus coagulansbacteria are delivered in the gastrointestinal tract of each subject perday. Treatments last at least about 10 days, e.g., about 10, 15, 20, 30,45, 60, 75, 90 or 120 days.

Results

Human patients suffering from or at risk of developing psoriasis havehigher levels of TNF-α than non-affected controls. Treatment withBacillus coagulans bacteria results in a decrease in serum TNF-α levelsin affected subjects.

Example 5 Medical Foods Containing Bacillus coagulans Bacteria

A “medical food” means a food which is formulated to be consumed oradministered enterically under the supervision of a physician and whichis intended for the specific dietary management of a disease orcondition for which distinctive nutritional requirements, based onrecognized scientific principles, are established by medical evaluation.(See, 21 USC 360ee(b)(3)). For subjects suffering from or at risk ofdeveloping an autoimmune disease, the compositions containing Bacilluscoagulans bacteria are nutritionally complete formulas of medical foods.Alternatively, the compositions containing Bacillus coagulans bacteriaare nutritionally incomplete formulas of medical foods.

Medical foods containing Bacillus coagulans bacteria are speciallyformulated and processed for subjects suffering from or at risk ofdeveloping an autoimmune disease, such as a subject who requires themedical as a major treatment modality. Typically, the medical foodscontaining Bacillus coagulans bacteria medical foods are formulated asan enteral nutrition product, i.e., it is provided through thegastrointestinal tract, taken by mouth, or provided through a tube orcatheter that delivers nutrients beyond the oral cavity or directly tothe stomach. The medical food is formulated to provide at least about1×10⁶ viable Bacillus coagulans bacteria in the gastrointestinal tractof a mammalian subject per day, based on a serving size of about 1 gramto about 2 grams of the medical food taken up to about twice a day. Themedical food also optionally includes a non-microbially derivedanti-fungal agent, an immunosuppressive agent, or a non-microbiallyderived anti-fungal agent and an immunosuppressive agent.

Subjects for whom medical foods containing Bacillus coagulans bacteriaare appropriate are identified by the presence or past incidence of oneor more symptoms of an autoimmune disease such as psoriasis, or by afamily history of the disease (one or more parents, grandparents orsiblings having one or more symptoms of an autoimmune disease).

Example 6 Use of Bacillus coagulans Bacteria in the Treatment of OtherAutoimmune Disorders

Twelve human patients with Crohn's disease were studied at a generalpractice clinic in Cleveland, Ohio over a one-month period. Patientswere provided with capsules containing Bacillus coagulans bacteria(1.5×10⁹ colony forming units (CFU)) and microcrystalline cellulose as acarrier, and instructed to take one capsule per day. There were norestrictions on the time of day of consumption. The treatment lasted onemonth; patients were observed at the beginning and end of the treatment.

Results after one month indicated that all 11 out of 12 patientsresponded well to the formulation. One patient dropped out withoutexplanation. The incidence of diarrhea was reduced by over 75% andabdominal pain and spasms were reduced significantly. Crohn's disease isdiagnosed symptomatically; thus, a significant reduction in the numberand severity of symptoms experienced each day is a notable improvementin individuals that suffer from this disease.

Other embodiments are within the following claims.

1. A method of reducing a symptom of psoriasis, comprising identifying apatient suffering from or at risk of developing psoriasis, and orallyadministering to said patient a composition comprising Bacilluscoagulans bacteria in an amount effective to reduce serum TNF-α levelsin said patient, wherein said bacteria is selected from the groupconsisting of GBI-20 (ATCC Designation Number PTA-6085), GBI-30 (ATCCDesignation Number PTA-6086), and GBI-40 (ATCC Designation NumberPTA-6087).
 2. The method of claim 1, wherein said composition furthercomprises an antifungal agent.
 3. The method of claim 2, wherein saidantifungal agent is selected from the group consisting of clotrimazole,fluconazole, itraconazole, ketoconazole, miconazole, nystatin,terbinafine, terconazole, and tioconazole.
 4. The method of claim 1,wherein said symptom is selected from the group consisting of scaling,blistering, skin lesions, itchiness, and joint pain.
 5. The method ofclaim 1, wherein said composition further comprises an immunosuppressiveagent.
 6. The method of claim 5, wherein said immunosuppressive agent isselected from the group consisting of methotrexate, cyclosporine,hydroxyurea, mycophenolate mofetil, sulfasalazine, and 6-thioguanine. 7.The method of claim 1, wherein said composition further comprises aretinoid.
 8. The method of claim 1, wherein said Bacillus coagulansbacteria are provided at a concentration of from about 1×10⁸ to about1×10¹⁰ colony forming units of viable bacteria.
 9. The method of claim1, wherein said Bacillus coagulans bacteria are provided at aconcentration of from about 1×10⁹ to about 2×10⁹ colony forming units ofviable bacteria.
 10. The method of claim 1, wherein the Bacilluscoagulans bacteria are in the form of spores.
 11. The method of claim 1,wherein the Bacillus coagulans bacteria are in the form of vegetativecells.
 12. The method of claim 1, wherein said composition furthercomprises an antibiotic agent, wherein said antibiotic agent is selectedfrom the group consisting of gentamicin, vancomycin, oxacillin,tetracycline, nitroflurantoin, chloramphenicol, clindamycin,trimethoprim sulfamethoxasole, cefaclor, cefadroxil, cefixime,cefprozil, ceftriaxone, cefuroxime, cephalexin, loracarbef, ampicillin,amoxicillin clavulanate, bacampicillin, cloxicillin, penicillin VK,ciprofloxacin, grepafloxacin, levofloxacin, lomefloxacin, norfloxacin,ofloxacin, sparfloxacin, trovafloxacin, azithromycin, and rythromycin.13. The method of claim 12, wherein said composition further comprisesan anti-fungal agent.
 14. The method of claim 1, wherein saidcomposition is orally administered about once every day for about 3days.
 15. The method of claim 1, wherein said composition is orallyadministered about once every day for about 7 days.
 16. The method ofclaim 1, wherein said composition further comprises a vitamin, amineral, or an antioxidant.
 17. The method of claim 1, wherein saidbacteria is GBI-20 (ATCC Designation Number PTA-6085).
 18. The method ofclaim 1, wherein said bacteria is GBI-30 (ATCC Designation NumberPTA-6086).
 19. The method of claim 1, wherein said bacteria is GBI-40(ATCC Designation Number PTA-6087).
 20. A method of reducing a symptomof Crohn's Disease, comprising identifying a patient suffering from orat risk of developing Crohn's Disease, and orally administering to saidpatient a composition comprising Bacillus coagulans bacteria in anamount effective to reduce serum TNF-α levels in said patient, whereinsaid bacteria is selected from the group consisting of GBI-20 (ATCCDesignation Number PTA-6085), GBI-30 (ATCC Designation Number PTA-6086),and GBI-40 (ATCC Designation Number PTA-6087).
 21. The method of claim20, wherein said symptom is selected from the group consisting ofdiarrhea, abdominal pain, rectal bleeding, fever, nausea, weight loss,lethargy and loss of appetite.
 22. The method of claim 20, wherein saidcomposition is orally administered about once every day for about 3days.
 23. The method of claim 20, wherein said composition is orallyadministered about once every day for about 7 days.
 24. The method ofclaim 20, wherein said composition further comprises a vitamin, amineral, or an antioxidant.
 25. The method of claim 20, wherein saidbacteria is GBI-20 (ATCC Designation Number PTA-6085).
 26. The method ofclaim 20, wherein said bacteria is GBI-30 (ATCC Designation NumberPTA-6086).
 27. The method of claim 20, wherein said bacteria is GBI-40(ATCC Designation Number PTA-6087).